Osteoporosis is a disease characterized by low bone mass and loss of bone tissue, resulting in weak and fragile bones. Net bone loss can be induced by various factors, e.g., low levels of estrogen, inadequate up take of calcium and vitamin D, and inflammation. Bone resorption is a major pathological factor in postmenopausal osteoporosis. Osteoporosis is a disorder of impaired bone strength that causes skeletal fragility and increases fracture risk (Theill, L E, et al. (2002) Annu Rev Immunol 20:795-823; Boyle, W J, et al. (2003) Nature 423; 337-342). Estrogen deficiency at menopause and androgen deficiency in men both cause an unbalanced increase in bone turnover, in which bone resorption exceeds bone formation. Relatively rapid bone loss occurs and is accompanied by the destruction of bone micro-architecture (Simonet, W S, et al. (1997) Cell 89:309-319; McClung, M, (2007) Arthritis Res Ther 9 Suppl 1:S3). In most instances, low bone mass is caused by an increase in the number of osteoclasts or by excessive osteoclast activity (Walsh, N C, et al. (2005) Immunol Rev 208:228-251). Osteoclasts are multinucleated giant cells that express tartrate-resistant acid phosphatase (TRAP) and calcitonin receptors. Osteoclast formation requires two factors: macrophage colony-stimulation factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL) (Takayanagi, H, et al. (2005) Immunol Rev 208:181-193; Ross, F P & Teitelbaum, S L, (2005) Immunol Rev 208:88-105). M-CSF, which mediates the survival and proliferation of monocyte/macrophage precursors, is produced primarily by stromal fibroblasts, osteoblasts, and activated T cells. RANK, is the sole signaling receptor for RANKL, which induces the development and activation of osteoclasts (Suda, T, et al., (1999) Endocr Rev 20:345-357). The in vivo significance of the RANKL-RANK signaling pathway has been verified by observations that the deficiency of either gene in mice causes severe osteoporosis (increased bone mass) and the disappearance of osteoclasts (Kong, Y Y, et al., (1999) Nature 397:315-323; Li, J, et al., (2000) Proc Nati Acad Sci USA 97:1566-1571). Several proinflammatory cytokines, such as TNF-α, IL-1β, IL-15, IL-17, and IL-23, induce the multinucleation of osteoclast precursors, or their commitment to the osteoclast phenotype, and may act synergistically with RANKL (Feldmann, M, et al. (2001) Curr Dir Autoimmun 3:188-199; O'Gradaigh, D, et al. (2004) Ann Rheum Dis 63:354-359; Sato, K, et al., (2006) J Exp Med 203:2673-2682; Ju, J H, et al., (2008) J Immunol 181:1507-1518).
The pleiotropic inflammatory cytokine IL-20, a member of the IL-10 family—IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26 (Blumberg, H, et al., (2001) Cell 104:9-19; Pestka, S, et al., (2004) Annu Rev Immunol 22:929-979)—is expressed in monocytes, epithelial cells, and endothelial cells. IL-20 acts on multiple cell types by activating a heterodimer receptor complex of either IL-20R1/IL-20R2 or IL-22R1/IL-20R2 (Dumoutier, L., et al., (2001) J Immunol 167:3545-3549). It is involved in various inflammatory diseases (Wei, C C, et al., (2006) J Biomed Sci 13:601-612), such as psoriasis (Blumberg, H, et al., (2001) Cell 104:9-19; Sa, S M, et al., (2007) J Immunol 178:2229-2240; Wei, C C, et al., (2005) Clin Immunol 117:65-72), rheumatoid arthritis (Hsu, Y H, et al., (2006) Arthritis Rheum 54:2722-2733), atherosclerosis (Caligiuri, G, et al. (2006) Arterioscler Thromb Vasc Biol 26:1929-1930; Chen, W Y, et al. (2006) Arterioscler Thromb Vasc Biol 26:2090-2095), ischemic stroke (Chen, W Y & Chang, M S, (2009) J Immunol 182:5003-5012), and renal failure (Li, H H, et al., (2008) Genes Immun 9:395-404). IL-20 is regulated by hypoxia and inflammatory stimuli such as IL-1β and LPS (Chen, W Y & Chang, M S, (2009) J Immunol 182:5003-5012; Otkjaer, K, et al., (2007) J Invest Dermatol). IL-20 has recently been reported (Heuze-Vourc'h, N, et al., (2005) Biochem Biophys Res Commun 333:470-475; Hsieh, M Y, et al., (2006) Genes Immun 7:234-242; Tritsaris, K, et al., (2007) Proc Natl Acad Sci USA 104:15364-15369) to have regulated angiogenesis. In experimental rheumatoid arthritis, IL-20 induces synovial fibroblasts to secrete MCP-1, IL-6, and IL-8, and it acts as a proinflammatory cytokine (Hsu, Y H, et al., (2006) Arthritis Rheum 54:2722-2733).
IL-20 has been shown to be involved in rheumatoid arthritis and IL-20 soluble receptors have been shown to block IL-20, which reduces the severity of collagen-induced arthritis (Hsu, Y H, et al., (2006) Arthritis Rheum 54:2722-2733). Therefore, IL-20 is a promoting factor during the progression of rheumatoid arthritis. Little is known, however, about the function of IL-20 in bone resorption, or about the function of IL-20 in RANKL-RANK signaling-mediated osteoclastogenesis.